Graduate Program

Biological Sciences

Degree Name

Master of Science (MS)

Semester of Degree Completion

2019

Thesis Director

Gopal R. Periyannan

Thesis Committee Member

Britto P. Nathan

Thesis Committee Member

Gary A. Bulla

Abstract

Glutamate carboxypeptidase II (GCPII) is a transmembrane zinc metalloprotease expressed in a number of organisms: from yeast to worm to humans. In humans, GCPII has been observed as a multifunctional protein and expressed in prostate, intestine, kidney, brain, tumor-associated neovasculature and other tissues as five paralogs. In the human small intestine, hGCPII is proposed to facilitate the folate absorption by cleaving terminal glutamate residues in dietary folates. Folates act as a cofactor in one-carbon metabolic pathways such as nucleotide synthesis, amino acid synthesis, DNA repair, and consequently involved in cell division and growth. The hGCPII homolog is found in the nematode Caenorhabditis elegans (cGCPII) as three paralogs and shares a high structural similarity with hGCPII. In this study, the C. elegans strains: wild-type (N2), and gcp-2 deletion mutant strains: RB1055 (gcp-2.1), TM6632 (gcp-2.2) and TM5414 (gcp-2.3) were used to investigate the role of gcp-2 in folate metabolism. This study shows that the gcp-2.1 and gcp-2.2 paralogs play a significant role in folate metabolism, reproduction, and embryonic and post-embryonic development in C. elegans. When the gcp-2 mutant worms were fed with a folate-deficient diet, it showed folate deficient phenotypes, infertility and growth retardation, as observed in mice and humans. This work establishes, for the first time, the relationship between GCPII and folate metabolism in C. elegans as proposed for human folate metabolism. This study demonstrates that C. elegans can be used as a genetically tractable model organism to invetigate the tissue-specific multifunctional roles of GCPII in development and reproduction of a multicellular organsim.

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